ABSTRACT Influenza A and B viral infections kill hundreds of thousands of people worldwide each year, costing society many billions of dollars in morbidity and disruption. This multicenter study of life-threatening influenza lower respiratory tract infection (LRTI) in children with acute respiratory failure, designed by an established group of pediatric critical care clinical trial investigators, was developed to evaluate how the host innate immune response is associated with disease susceptibility and clinical outcome. We hypothesize that innate immune components that mediate recognition of influenza, including Toll-like receptors (TLRs 2, 3, 7, 8, and 9), retinoic-acid inducible protein (RIG-I), the collectins surfactant proteins A and D (SP-A, SP-D) and mannose binding lectin (MBL), Vitamin D related genes (VDR), and genes influencing down-stream cytokines such as interferon-alpha (IFN-[unreadable]), play important roles in host susceptibility to severe influenza infection. In addition, we hypothesize that specific features of the innate immune response of these children on presentation to the ICU will predict disease severity and duration of recovery. We will test these hypotheses by recruiting a representative sample of 240 critically ill children with life-threatening influenza LRTI, serially testing important inflammatory and immune mediators from peripheral blood and lung, performing sensitive tests to identify coinfection, and obtaining DNA, to achieve 3 Specific Aims: 1.) To compare the inflammatory and innate immune response of children with life-threatening LRTI from influenza infection alone to 7 control groups including children with healthy lungs, severe LRTI from respiratory syncytial virus, and LRTI from influenza coinfected with important viral and bacterial subgroups such as S. aureus, 2.) To assess how the innate immune response is associated with disease severity and duration of disease recovery focusing on innate immune responsiveness (immunoparalysis), Interleukin 8 (a predictor of outcome for sepsis and acute lung injury), Vitamin D, and SP-A and SP-D (important for lung function and viral immunity), and 3.) To identify associations between life-threatening influenza LRI susceptibility and polymorphisms in 11 important innate immunity genes related to the immune response to influenza (TLRs 2, 3, 7, 8, and 9, VDR, SFTPA1, SFTPA2, SFTPD, RIG-1, MBL) and to perform an exploratory analysis of over 69 additional genes related to the type I interferon response. Our approach will entail engagement of 31 sites across the Pediatric Acute Lung Injury and Sepsis Investigator's (PALISI) Network, a well-established consortium of clinical investigators across pediatric ICUs in the US and Canada with a proven track record of productivity. Ultimately, this project will provide a more sophisticated understanding of the role of innate immune genes and immunoparalysis in influenza infection, providing new targets for future preventive (immune adjuvant and/or vaccine) and therapeutic approaches to decrease influenza-related morbidity and mortality.